tetano
Editor, Senior Moderator
Antiviral Res
. 2022 Oct 31;105455.
doi: 10.1016/j.antiviral.2022.105455. Online ahead of print.
Effect of E23 G/K, F36V, N37T, E119D, and E199G polymerase acidic protein substitutions on the replication and baloxavir susceptibility of influenza B viruses
Philippe Noriel Q Pascua[SUP] 1 [/SUP], Jeremy C Jones[SUP] 1 [/SUP], Richard J Webby[SUP] 1 [/SUP], Elena A Govorkova[SUP] 2 [/SUP]
Affiliations
Abstract
Baloxavir marboxil (baloxavir) is a highly effective, single-dose influenza therapeutic. Identification of molecular markers in the target polymerase acidic (PA) protein that can diminish baloxavir efficacy is an ongoing goal of the scientific community. In this study, we generated recombinant Victoria-lineage and Yamagata-lineage influenza B viruses (IBVs) containing 6 substitutions (E23G/K, F36V, N37T, E119D, and E199G) spanning the endonuclease domain of the PA. Although 5 of these PA substitutions negatively impacted in vitro polymerase activity and replication kinetics, particularly in the Victoria-lineage IBV background, viruses with E119D exhibited activity levels comparable to those of wild-type viruses. Moreover, only E119D moderately decreased the susceptibility of IBVs to baloxavir (resulting in ∼2.0-fold-2.6-fold elevated EC[SUB]50[/SUB]s); viruses with the other substitutions exhibited normal drug inhibition. These results show that E119D may reduce the baloxavir susceptibility of IBVs without compromising their replicative fitness. Overall, this study expands the molecular landscape of PA substitutions affecting baloxavir efficacy against IBV.
Keywords: Antivirals; Baloxavir; Baloxavir resistance; Influenza B virus; Polymerase.
. 2022 Oct 31;105455.
doi: 10.1016/j.antiviral.2022.105455. Online ahead of print.
Effect of E23 G/K, F36V, N37T, E119D, and E199G polymerase acidic protein substitutions on the replication and baloxavir susceptibility of influenza B viruses
Philippe Noriel Q Pascua[SUP] 1 [/SUP], Jeremy C Jones[SUP] 1 [/SUP], Richard J Webby[SUP] 1 [/SUP], Elena A Govorkova[SUP] 2 [/SUP]
Affiliations
- PMID: 36328072
- DOI: 10.1016/j.antiviral.2022.105455
Abstract
Baloxavir marboxil (baloxavir) is a highly effective, single-dose influenza therapeutic. Identification of molecular markers in the target polymerase acidic (PA) protein that can diminish baloxavir efficacy is an ongoing goal of the scientific community. In this study, we generated recombinant Victoria-lineage and Yamagata-lineage influenza B viruses (IBVs) containing 6 substitutions (E23G/K, F36V, N37T, E119D, and E199G) spanning the endonuclease domain of the PA. Although 5 of these PA substitutions negatively impacted in vitro polymerase activity and replication kinetics, particularly in the Victoria-lineage IBV background, viruses with E119D exhibited activity levels comparable to those of wild-type viruses. Moreover, only E119D moderately decreased the susceptibility of IBVs to baloxavir (resulting in ∼2.0-fold-2.6-fold elevated EC[SUB]50[/SUB]s); viruses with the other substitutions exhibited normal drug inhibition. These results show that E119D may reduce the baloxavir susceptibility of IBVs without compromising their replicative fitness. Overall, this study expands the molecular landscape of PA substitutions affecting baloxavir efficacy against IBV.
Keywords: Antivirals; Baloxavir; Baloxavir resistance; Influenza B virus; Polymerase.